Butein sensitizes human hepatoma cells to TRAIL-induced apoptosis via extracellular signal-regulated kinase/Sp1-dependent DR5 upregulation and NF-κB inactivation

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Title
Butein sensitizes human hepatoma cells to TRAIL-induced apoptosis via extracellular signal-regulated kinase/Sp1-dependent DR5 upregulation and NF-κB inactivation
Author(s)
D O Moon; Mun-Ock Kim; Y H Choi; G Y Kim
Bibliographic Citation
Molecular Cancer Therapeutics, vol. 9, no. 6, pp. 1583-1595
Publication Year
2010
Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces cell death in various types of cancer cells but has little or no effect on normal cells. Human hepatoma cells are resistant to TRAIL-induced apoptosis. Although butein is known to mediate anticancer, anti-inflammatory, and antioxidant activities, little is known about the mechanism of butein in terms of TRAIL-induced apoptosis of human hepatoma cells. In this study, we determined that butein enhances TRAIL-induced apoptosis in hepatoma cells through upregulation of DR5. Luciferase analysis showed that a 5′-flanking region containing four Sp1-binding sites within the DR5 promoter was enhanced by butein (-305/-300). Electrophoretic mobility shift assays and chromatin immunoprecipitation studies were used to analyze the elevation of Sp1 binding to DR5 promoter sites by butein. Point mutations of the Sp1-binding site also attenuated promoter activity. Furthermore, pre-treatment of the blocking chimeric antibody and small interfering RNA for DR5 significantly suppressed TRAIL-mediated apoptosis by butein in Hep3B cells. Butein also stimulated extracellular signal-regulated kinase (ERK) activation, and the ERK inhibitor PD98059 blocked butein-induced DR5 expression and suppressed binding of Sp1 to the DR5 promoter. Additionally, generation of reactive oxygen species had no effect on cell viability, although pretreatment with N-acetyl-L-cysteine or glutathione inhibited combined treatment-induced reactive oxygen species. Indeed, butein repressed the TRAIL-mediated activation of NF-κB and decreased its transcriptional activity. Our results suggest that butein could sensitize certain human hepatoma cells to TRAIL-induced apoptosis through stimulating its death signaling and by repressing the survival function in these cells.
ISSN
1535-7163
Publisher
Amer Assoc Cancer Research
DOI
http://dx.doi.org/10.1158/1535-7163.MCT-09-0942
Type
Article
Appears in Collections:
Ochang Branch Institute > Natural Medicine Research Center > 1. Journal Articles
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